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The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H₁ receptor (H₁R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H₁R complex with doxepin, a first-generation H₁R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp 428^6.48, a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H₁R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys 191^5.39 and/or Lys 179^ECL2 …